Ultraviolet B radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. This biologic property contributes in a major way to the growth and development of UV-induced skin cancers. Toll-like receptors, one component of innate immune system are intricately associated with a number of dermatologic conditions. Recent experiments from my laboratory suggest that innate immunity, especially toll like receptor 4 (TLR4), may play an important role in photoimmunological processes. The hypothesis that I will test in this proposal is that UV-induced regulatory T-cells (Treg) act to inhibit the development and/or function of IFN-D producing T-cells (TC1) but not IL-17 producing T-cells (TC17). Since TLR4 deficiency directs the cell-mediated immune response towards IL-17 producing T-cells, the inability of UVinduced Treg cells to inhibit Tc17 cells results in fewer UV-induced tumors in TLR4 deficient mice. To address these issues, three specific aims are proposed. First, experiments will be conducted to assess whether regulatory T-cells develop in TLR4 knockout mice after UVB radiation exposure, and, if so, their phenotype and cytokine profile will be characterized. Then, studies will be performed to determine why regulatory T-cells either do not develop or are non-functional in TLR4 deficient mice. Finally, the implications of resistance of TLR4 deficient mice to UVB-induced immunosuppression for photocarcinogenesis will be assessed. The ultimate goal of these studies is to identify genetic loci that are involved in UV-induced immune suppression and to exploit that knowledge to develop immunopreventive and immunotherapeutic approaches for photoimmunosuppression.